Transcriptional regulation and therapeutic modulation of cytotoxic function in tumour-infiltrating CD4+ T cells

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The immune system may hold the key to combating cancer. Recent cancer immunotherapy approaches have been focused on boosting or re-invigorating cytotoxic CD8+ T cell function. However, the proportion of patients that do not respond to therapy remains high and some tumours are not targeted by CD8+ T cells. There is growing recognition that CD4+ T helper cells can also acquire cytotoxic effector function, and that these cells form a key component of the response to cancer and viral infection. However, our understanding of cytotoxic CD4+ T cell derivation and function lags significantly behind that of their CD8+ counterparts and other CD4+ T cell lineages. Identifying factors that regulate the differentiation and function of cytotoxic CD4+ T cells would provide new opportunities to boost the immune response to cancer and viral infection. We propose to combine genomics and cancer immunology approaches to identify regulatory proteins that control the differentiation and function of cytotoxic CD4+ T cells in tumours and how these mechanisms may be targeted to harness the activity of these cells.Building on previous work from our labs, we will use genetically modified tumour models to identify the genes through which transcriptional regulators control differentiation of cytotoxic CD4+ T cell precursors. We will also define the nature of a checkpoint that prevents acquisition of cytotoxic function by precursor cells in untreated tumours. Finally, we will determine whether these regulatory mechanisms can be targeted to promote cytotoxic CD4+ T cell function and tumour immunity.This work will provide knowledge of the factors that control cytotoxic CD4+ T cell function and identify targets through which the activity of these cells can be harnessed in patients.